Hyperinnervation of the airways in transgenic mice overexpressing nerve growth factor.
Neuropeptides released from sensory nerve endings are potential mediators of airway inflammation in asthma and lung injury induced by inhalation of respiratory irritants. To develop an in vivo model for assessing the contribution of neurogenic inflammation in these processes, we have generated transgenic mice with altered innervation of the lung. To generate mice with an increased innervation of the airways, we placed the gene that encodes nerve growth factor (NGF) under control of the lung-specific Clara-cell secretory protein (CCSP) promoter. Two lineages of CCSP-NGF transgenic mice overexpressed NGF in the lung and developed a hyperinnervation of the airways. Immunohistochemistry for substance P, a substance P enzyme immunoassay, and catecholamine histofluorescence indicated that both tachykinin-containing sensory fibers and sympathetic fibers were increased around the airways of CCSP-NGF mice. Treatment of CCSP-NGF mice with the sympathetic-specific neurotoxin 6-hydroxydopamine (6-OHDA) eliminated the sympathetic component of the airway innervation, leaving a specific hyperinnervation by tachykinin-containing sensory fibers. CCSP-NGF mice were more sensitive than normal mice to capsaicin-induced increases in respiratory system resistance, demonstrating that the increased sensory innervation led to a change in airway function. We conclude that NGF overexpression from a lung-specific promoter produces anatomic and functional changes in lung innervation, and that CCSP-NGF mice will be useful for studying the role of neurogenic inflammation in airway disease.
Hoyle
G W
GW
Department of Medicine and Pediatrics, Tulane University Medical Center, New Orleans, Louisiana 70112, USA. ghoyle@tmc.tulane.edu
Graham
R M
RM
Finkelstein
J B
JB
Nguyen
K P
KP
Gozal
D
D
Friedman
M
M
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002395:Catecholamines / Q000032:analysis; D004195:Disease Models, Animal; D015870:Gene Expression; D008168:Lung / Q000737:chemistry / Q000294:innervation* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000032:analysis / Q000235:genetics*; D009475:Neurons, Afferent; D016627:Oxidopamine / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D013373:Substance P / Q000032:analysis; D014598:Uteroglobin
D002395:Catecholamines; D009414:Nerve Growth Factors; D011506:Proteins; D012333:RNA, Messenger; C556390:Scgb1a1 protein, mouse; D013373:Substance P; D016627:Oxidopamine; D014598:Uteroglobin; D002211:Capsaicin